RU2401262C2 - Alkylaminothiazole derivatives, synthesis method thereof and use thereof in therapy - Google Patents

Abstract

FIELD: chemistry.

SUBSTANCE: invention relates to compounds of formula (I) in form of base or a pharmaceutically acceptable addition salt with an acid. The disclosed compounds have β-amyloid peptide(β-A4) formation inhibiting properties. In formula

(I), R₁ denotes: C_1-6-alkyl or phenyl; where said phenyl groups are substituted with two substitutes selected from halogen atoms; R₁ and R_2' independently denote a hydrogen atom or a hydroxy group; R3 denotes C₁-₆-alkyl; one or another of radicals R₄ and R₅ is a group Z

and one or another of radicals R₄ and R₅ is a -C(X)R₆ group; G denotes a single bond; Y denotes a single bond, an oxygen atom, a sulphur atom, a C_1-4-alkylene group; A and B independently denote a hydrogen atom, a halogen, trifluoromethyl, trifluoromethoxy group; provided that if Y denotes a single bond or an oxygen atom and if group Z is a

type group, A does not denote a hydrogen atom; X denotes an oxygen atom; R₆ denotes a C_1-6alkoxy group. The invention also relates to a method for synthesis of formula (I) compounds, to a medicinal agent and a pharmaceutical composition based on said compounds, and to use of formula (I) compounds in preparing the medicinal agent.

EFFECT: increased effectiveness of using said derivatives.

6 cl, 1 tbl, 31 ex

Description

The object of the present invention are derivatives of alkylaminothiazole, their preparation and their use in therapy.

Derivatives of alkylaminothiazole are already known, described in documents WO 03/014095 A, WO 2004/009565 A and WO 2004/033439 A, which are inhibitors of the formation of β-amyloid peptide (β-A4).

There is always a need for the search and development of substances that are inhibitors of the formation of β-amyloid peptide (β-A4). The compounds of the invention fulfill this purpose.

The first object of the invention are compounds corresponding to General formula (I):

wherein:

R ₁ means: either C _1-6 alkyl, optionally substituted with one, two or three substituents selected from: halogen, trifluoromethyl, hydroxy, C _1-6 alkoxy, C _1-6 thioalkyl, thiophene or phenyl; or C _3-7 -cycloalkyl, thiophene, benzothiophene, pyridinyl, furanyl or phenyl; moreover, the above-mentioned phenyl groups, in known cases, can be substituted with one, two or three substituents selected from: a halogen atom, a C _1-6 alkyl group, a C _1-6 alkoxy group, a hydroxy group, a methylenedioxy group, a phenoxy group or a benzyloxy group, or trifluoromethyl;

R ₂ and R ₂ ^′ are, independently of one another, a hydrogen atom, a halogen atom, a hydroxy group, a C _1-3 alkoxy group, a C _1-3 alkyl, a C _3-7 cycloalkyl, an O — C (O) - group C _1-6 -alkyl, or R ₂ and R ₂ ^' together form an oxo group;

R ₃ represents a hydrogen atom, C _1-6 alkyl, optionally substituted with a hydroxyl group, C _1-6 cycloalkyl or C _1-3 alkoxy group;

one or the other of the radicals R ₄ and R ₅ represents a group Z

and one or the other of R ₄ and R ₅ represents a —C (X) R ₆ group;

G is a single bond or a —CH ₂ - group;

Y is a single bond, an oxygen atom, a sulfur atom, a C _1-4 alkylene group or —N (W) -, wherein the C _1-4 alkylene group is, in known cases, substituted with a hydroxy group or a C _1-3 alkoxy group;

W denotes either a hydrogen atom or C _1-3 -alkyl, in certain cases substituted by phenyl, or phenyl;

A and B are, independently of one another, a hydrogen atom, a halogen atom, a hydroxy group, a C _1-3 alkyl, a C _1-3 alkoxy group, trifluoromethyl, trifluoromethoxy group or —O — CHF ₂ ; provided that if Y represents a single bond or an oxygen atom and if the Z group represents a group of the type

then A is different from the hydrogen atom;

X represents an oxygen atom or a sulfur atom;

R ₆ is a C _1-6 alkoxy group, a hydroxy group or —NR ₇ R ₈ ; wherein the C _1-6 alkoxy group is optionally substituted with phenyl;

R ₇ and R ₈ are, independently of one another, either a hydrogen atom; or a C _1-6 alkyl group, optionally substituted with C _3-7 cycloalkyl, C _3-7 cycloalkenyl, C _1-3 alkoxy, phenyl, morpholinyl or pyridinyl; either a C _3-7 cycloalkyl group, a C _1-6 alkoxy group or phenyl; moreover, the above-mentioned C _3-7 cycloalkyl and phenyl groups, in known cases, are substituted by one or two groups selected from a halogen atom, a hydroxy group, a C _1-3 alkyl or a C _1-3 alkoxy group; or

R ₇ and R ₈ together with the nitrogen atom that carries them form an aziridine, azetidine, pyrrolidine, piperidine, morpholine or benzopiperidine ring.

Among the compounds of general formula (I), the first subgroup of compounds is formed by compounds for which R ₁ is C _1-6 alkyl or phenyl, optionally substituted with one, two or three halogen atoms.

Among the compounds of general formula (I), a second subgroup of compounds is formed by compounds for which R ₂ and R ₂ ^′ are, independently of one another, a hydrogen atom, a hydroxy group, or R ₂ and R ₂ ^′ together form an oxo group.

Among the compounds of general formula (I), a third subgroup of compounds is formed by compounds for which R ₃ is C _1-6 -alkyl.

Among the compounds of general formula (I), a fourth subgroup of compounds is formed by compounds for which:

one or the other of the radicals R ₄ and R ₅ represents a group Z

and one or the other of R ₄ and R ₅ represents a —C (X) R ₆ group;

G is a single bond;

Y represents a single bond, an oxygen atom, sulfur, a C _1-4 alkylene group, more specifically a methylene group;

A and B mean, independently of one another, a hydrogen atom, a halogen, more specifically a fluorine, a trifluoromethyl group, a trifluoromethoxy group; provided that if Y represents a single bond or an oxygen atom and if the Z group represents a group of the type

then A is different from the hydrogen atom;

X represents an oxygen atom or a sulfur atom;

R ₆ represents a C _1-6 alkoxy group, more specifically a methoxy group or ethoxy group.

Compounds for which at the same time A, B, W, X, Y, Z, R ₁ , R ₂ , R ₂ ^' , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ are as defined in the above subgroups of compounds form the fifth subgroup.

Among the compounds of general formula (I) and the aforementioned subgroups, a sixth subgroup of compounds is formed by compounds for which:

R ₁ is C _1-4 alkyl, preferably isopropyl or tert- butyl or phenyl substituted with two fluorine atoms; and / or

R ₂ represents a hydrogen atom or a hydroxy group and R ₂ ^′ represents a hydrogen atom; and / or

R ₃ is C _1-4 alkyl, preferably methyl, ethyl or propyl; and / or

X represents a hydrogen atom.

In the framework of the present invention

- by C _tz, where t and z take values from 1 to 7, we mean a carbon chain capable of containing from t to z carbon atoms, for example a C _1-3 carbon chain, which may contain from 1 to 3 carbon atoms, C _{3 -6} carbon chain, which may contain from 3 to 6 carbon atoms,

- by alkyl is meant a saturated aliphatic group, linear or branched, for example, a C _1-6 -alkyl group is a carbon chain containing from 1 to 6 carbon atoms, linear or branched, more specifically, methyl, ethyl, propyl, isopropyl, butyl , isobutyl, sec -butyl, tert- butyl, ... preferably methyl, ethyl, propyl or isopropyl;

- alkylene is understood to mean a divalent saturated alkyl group, linear or branched, for example, C _1-3 alkylene is a divalent carbon chain containing from 1 to 3 carbon atoms, linear or branched, more specifically, methylene, ethylene, isopropylene, propylene;

- cycloalkyl means a cyclic alkyl group, for example, C _3-7 cycloalkyl represents a cyclic carbon chain containing from 3 to 7 carbon atoms, more specifically cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, preferably cyclopentyl or cyclohexyl;

- cycloalkenyl means a mono- or polyunsaturated cyclic alkyl group, for example, C _3-7 cycloalkenyl is a mono- or polyunsaturated cyclic carbon chain containing from 3 to 7 carbon atoms, more specifically, cyclopropenyl, cyclobutenyl, cyclopentenyl, cyclohexenyl, cycloheptenyl preferably cyclopentenyl or cyclohexenyl;

- under thioalkyl understand a group of S-alkyl with a saturated aliphatic chain, linear or branched;

- under alkoxygroup understand the group-O-alkyl with a saturated aliphatic chain, linear or branched;

- a halogen atom means fluorine, chlorine, bromine or iodine;

- “R ₂ and R ₂ ^' together form an oxo group” means a group such that:

and

and

такова, что один из атомов углерода ароматического цикла может быть заменен атомом азота в положении, в котором нет заместителя А или В.- in group Z an aromatic group

such that one of the carbon atoms of the aromatic ring can be replaced by a nitrogen atom in a position in which there is no substituent A or B.

Compounds of general formula (I) may contain one or more asymmetric carbon atoms. Therefore, they can exist in the form of enatiomers or diastereoisomers. The enantiomers, diastereoisomers, and mixtures thereof, including racemic mixtures, are included in the invention. When the carbon atom bearing R ₂ and R ₂ ^′ and / or the carbon atom bearing R ₃ are asymmetric, compounds of the general formula (I) in which the carbon atom carrying R ₂ and R ₂ ^′ are configured (S ) and / or a carbon atom bearing R ₃ has the configuration (S).

The compounds of formula (I) may exist in the form of bases or acid addition salts. Such addition salts are included in the invention.

The above salts are prepared predominantly with pharmaceutically acceptable acids, but salts of other acids used, for example, for the purification or isolation of compounds of formula (I) are also included in the invention.

The compounds of general formula (I) may be in the form of hydrates or solvates, namely in the form of associates or compounds with one or more water molecules, or with a solvent. Such hydrates and solvates are equally included in the invention.

The second object of the present invention are methods for producing compounds of formula (I).

So, these compounds can be obtained by methods illustrated in the schemes below, the operating conditions of which are common to a person skilled in the art.

By the term “protecting group” is meant a group that makes it possible to interfere with the reactivity of a functional group or position during a chemical reaction that may affect them and that recreates the molecule after breaking the chemical bond according to methods known to those skilled in the art. Examples of protective groups, as well as methods for protecting and deprotecting, are given, among other things, in the monograph Protective groups in Organic Synthesis, Greene et coll., 2 ^nd Ed. (John Wiley & Sons, Inc., New York).

The values of A, B, W, X, Y, Z, R ₁ , R _2, R ₂ ^' , R ₃ , R ₄ , R ₅ , R ₆ , R ₇ and R ₈ in the compounds of formulas (II) to (XVIII) below are those defined for compounds of formula (I), unless otherwise specified.

According to Scheme 1 below, a compound of formula (I) can be prepared by peptide binding of 2-aminothiazole of formula (III) with an acylamino acid of formula (II) under operating conditions known to the skilled person, for example, in the presence of benzotriazol-1-yloxy-tris hexafluorophosphate ( pyrrolidino) phosphonium (RuBOP) or benzotriazol-1-yloxy-tris (dimethylamino) phosphonium hexafluorophosphate (BOP) and N-ethylmorpholine or N-methylmorpholine in an inert solvent such as N, N-dimethylformamide, which can be acetonitrile or dichloromethane vary from 0 ° C to room temperature.

A compound of formula (II) can be prepared by peptide binding of a compound of formula (IV) with a protected acid of formula (V) in which Pg is a protecting group, for example benzyl, according to methods known to those skilled in the art, such as those described above. The compound thus obtained is then deprotected. In the case where the protecting group is benzyl, the compound is pre-hydrogenated to obtain a compound of formula (II), preferably in the presence of palladium on carbon in absolute ethanol at atmospheric pressure of hydrogen at room temperature.

DIAGRAM 1

Alternatively, the compound of formula (I) can be obtained according to scheme 2.

According to Scheme 2 below, a compound of formula (I) can be prepared by peptide binding of a compound of formula (IV) with an amine of formula (VI) according to methods known to those skilled in the art, such as, for example, in the presence of hydroxybenzotriazole GBT hydrate (HOBt) and 1- hydrochloride ethyl 3- (3-dimethylaminopropyl) carbodiimide (EDAK, HCl) (EDAK, HCl).

DIAGRAM 2

The compound of formula (VI) can be obtained by peptide binding of 2-aminothiazole of formula (III) with a protected amine of formula (VII), in which Pg is a protecting group, for example, N- tert- butyloxycarbonyl (BOC) (Boc), according to methods known specialist, such as those described above. The compound thus obtained is then deprotected. In the case where the protective group is BOC, in order to obtain a compound of formula (VI), deprotection is carried out by acid hydrolysis in the presence of gaseous hydrochloric acid dissolved in an anhydrous solvent or trifluoroacetic acid.

Compounds of formula (I) in which R ₂ and R ₂ ^′ form an oxo group can be prepared by oxidation of a compound of formula (I) in which R ₂ or R ₂ ^′ is a hydroxy group. The reaction can be carried out under conditions known to the person skilled in the art, for example, with Dess Martin reagent. Similarly, these compounds can be prepared by directly linking a keto acid of formula IV), in which R ₂ and R ₂ ^′ together form an oxo group, with an amine of formula (VI) under conditions known to those skilled in the art. Methods for producing such keto acids are known to those skilled in the art.

The compounds of formula (III) in which R ₄ = —C (O) —R ₆ , wherein R ₆ is a C _1-6 alkoxy group, can be prepared according to Scheme 3 below.

DIAGRAM 3

According to Scheme 3, a compound of formula (III) can be prepared by reacting an aldehyde of formula (VIII) in which R ₅ is as defined above with methyldichloroacetate of formula (IX) in which R ₆ is a C _1-6 alkoxy group, in known cases, substituted by phenyl and, for example, sodium methylate or ethylate at 0 ° C according to the adaptation of the method described by Takeda (Bull. Chem. Soc. Jp., 1970, p. 2997). To obtain a compound of formula (III), the resulting mixture of products (X) and (XI) is treated with thiourea in the presence of, for example, methanol or ethanol under reflux for 4 or 8 hours.

Compounds of formula (III) in which R ₄ = —C (O) —R ₆ , wherein R ₆ is a hydroxy group, can be prepared by hydrolysis of the above compounds for which R ₆ is a C _1-6 alkoxy group, in known cases substituted by phenyl under conditions known to those skilled in the art.

A compound of formula (III) in which R ₅ = —C (O) —R ₆ , wherein R ₆ is a C _1-6 alkoxy group, can be prepared according to Scheme 4 below.

DIAGRAM 4

According to Scheme 4, a compound of formula (III) can be obtained by bromination of a β-keto ester of formula (XIII) in which R ₆ represents a C _1-6 alkoxy group, optionally substituted with phenyl, to give a compound of formula (XII), and a subsequent thiourea reaction according to an adaptation of the method described by Barton et al. (Barton et coll.) (JCS Perkin I, 1982, p. 159).

A β-keto ester of formula (XIII) can be prepared by reacting a ketone of formula (XIV) with a dialkyl carbonate of formula (XVI) in which R ₆ is a C _1-6 alkoxy group, optionally substituted with phenyl, according to an adaptation of the method described by Crombie with colleagues (L. Crombie et coll.) (JCS Perkin Trans I, 1987, p. 323). Similarly, a β-keto ester of formula (XIII) can be prepared by reacting an acid of formula (XV) activated with carbonyldiimidazole (CDI) (CDI) with a malonate of formula (XVIa) in which R ₆ is a C _1-6 alkoxy group, in known cases, substituted with phenyl, according to an adaptation of the method described, for example, by Brooks et al. (DW Brooks et coll.) (Angew. Chem. Int. Ed., 1979, p. 72).

A compound of formula (III) in which R ₅ = —C (O) —R ₆ , wherein R ₆ is a hydroxy group, can be prepared by hydrolysis of the aforementioned compounds for which R ₆ is a C _1-6 alkoxy group, under conditions known to the specialist.

A compound of formula (III) in which R ₄ or R ₅ is —C (O) —NR ₇ R ₈ can be prepared according to scheme 5.

DIAGRAM 5

According to Scheme 5, a compound of formula (III) is prepared by peptide binding of a compound of formula (XVII) in which R ₅ or R ₄ is a carboxyl group and Pg is a protective group such as BOC with a compound of formula (XVIII) in the presence of, for example GBT and (EDAC, Hcl). The compound thus obtained is freed from protection under conditions known to the skilled person. A compound of formula (XVII) in which Pg is BOC can be obtained by protecting a compound of formula (III) in which R ₄ or R ₅ is a —C (O) R ₆ group and R ₆ is C _{1- The 6-} alkoxy group, in known cases substituted with phenyl, by exposure to di- tert-butyl dicarbonate in anhydrous terahydrofuran in the presence of dimethylaminopyridine at room temperature and subsequent hydrolysis of the carboxylate under conditions known to the skilled person, for example, with lithium hydroxide in tetrahydrofuran / water 7: 3 mixture ( vol./about.) at temperature re 60 ° C.

Compounds of general formula (I) in which R ₄ or R ₅ represents a group —C (X) R ₆ and X = S can be prepared from the corresponding compounds of general formulas (I) or (III) in which R ₄ or R ₅ represents a group —C (X) R ₆ and X = O, by converting a C (O) group to a CS group, for example, using Lawesson's reagent according to a method similar to that described by Cava and colleagues (MP Cava et coll) in Tetrahedron 1985, p.5061.

In schemes 1-5, the starting compounds and reagents, in particular, compounds of formulas (III), (IV), (V), (VII), (VIII), (IX), (XIV), (XV), (XVI) , (XVIa), (XVII) and (XVIII), when the method for their preparation is not described, are commercially available or described in the literature, or can be obtained by methods that are described in the literature or which are known to those skilled in the art.

For example, compounds of formula (IV) in which R ₂ or R ₂ ^′ is a hydroxy group can be prepared by attaching trimethylsilyl cyanide to an aldehyde according to an adaptation of the method described by Evans et al. (DA Evans et coll.) (JCS, Chem. Comm. 1973 , p. 55) or the action of sodium nitrite on an alpha amino acid according to an adaptation of the method described by Shinn et al. (I. Shinn et coll.) (J. Org. Chem., 2000, p. 7667).

For example, compounds of formula (XV) in which Y = O can be prepared according to an adaptation of the method described by Sindel et al. (Collect. Csech. Tchecosl., 1982, p. 72) or Atkison et al. ( Atkison et coll.) (J. Med. Chem., 1983, p. 1553).

For example, compounds of formula (XV) in which Y is a C _1-4 alkylene type group can be prepared, for example, according to an adaptation of the method described by Crow et al. (Crow et coll.) (Austral. J. Chem., 1981, p. 1037), or alternatively, by the Suzuki reaction according to an adaptation of the method described by Chahen et al. (Synlett, 2003, p. 1668).

For example, compounds of formula (XV) in which Y = S can be prepared according to the method described by Goldberg (Chem. Ber., 1994, p. 4526).

For example, compounds of formula (XV) in which Y = N (W) can be prepared according to the method described by Chan et al. (Tetrahedron Letters, 1998, p.2933) or Chamain (Tetrahedron Letters, 1998, p. 4179) or by Hugh et al. (Huwe et coll.) (Tetrahedron Letters, 1999, p. 683).

For example, compounds of formula (XV) in which Y is a single bond can be prepared by a Suzuki reaction under conditions known to one skilled in the art, for example, according to the method described by Deng et al. (Deng et coll.) Synthesis, 2003, p .337 or Meyer et al. (Meier et coll.) Synthesis, 2003, p.551.

For example, compounds of formula (VIII) can be prepared by reducing the compounds of formula (XV) under conditions known to those skilled in the art.

When a functional group of a compound is reactive, for example, when R ₁ contains a hydroxy group, it may require prior protection before the reaction. The specialist will be able to easily determine the need for preliminary protection.

The following examples describe the preparation of certain compounds of the invention. These examples are not restrictive and only illustrate the invention.

The numbers of the compounds given as examples correspond to the numbers given in the table below. Elemental microanalysis and analysis by NMR, IR spectrometry or LC-MS (LC-MS) (liquid chromatography in combination with mass spectrometry) confirm the structure of the compounds obtained.

Example 1: 2- {2- (S) - [2- (3,5-difluorophenyl) acetylamino] pentanoyl} amino-5- [2- (4-fluorophenoxy) phenyl] thiazole-4-methylcarboxylate

Example 1.1: 2- (4-fluorophenoxy) benzoic acid

To a mixture of 120 g of 2-iodobenzoic acid, 1 g of powdered copper and 54.4 g of 4-fluorophenol in 200 ml of N, N-dimethylformamide, 100 g of potassium carbonate was slowly added. Warm at 160 ° C for 4 hours, then allow to cool before evaporation. The residue is extracted with distilled water, acidified with an aqueous solution of 1 N. hydrochloric acid, then extracted with ethyl acetate. The organic phase is washed with a saturated solution of sodium chloride, dried over anhydrous sodium sulfate, and then concentrated. The expected product is crystallized from diethyl ether / pentane. 50 g of a white solid are obtained.

LC / MS: MH ⁺ = 233

Example 1.2: 2- (4-fluorophenoxy) -O, N-dimethylbenzamide

To a solution of 50 g of 2- (4-fluorophenoxy) benzoic acid obtained in step 1.1 in 450 ml of N, N-dimethylformamide was added 29.7 g of hydroxybenzotriazole hydrate, then 37 g (EDAC, HCl), 19 g (O, N -dimethylhydroxylamine, HCl) and 19.4 g of N-methylmorpholine. Stirred at room temperature for 16 hours. Evaporate, remove with ethyl acetate and wash 2 times with a saturated aqueous solution of sodium chloride, 1 time with distilled water, 1 time with an aqueous solution of 1 M potassium hydrogen sulfate, then with a saturated aqueous solution of sodium chloride. Dried over anhydrous sodium sulfate, then concentrated. Obtain 49 g of colored oil, which is used in this state subsequently.

LC / MS: MH ⁺ = 276

Example 1.3: 2- (4-fluorophenoxy) benzaldehyde

To a 100 ml of a solution of 1M lithium aluminum hydride in tetrahydrofuran at 0 ° C was added dropwise 48.5 g of 2- (4-fluorophenoxy) -O, N-dimethylbenzamide obtained in step 1.2 in 300 ml of anhydrous tetrahydrofuran. Stirred at 0 ° C for 1 hour, then 40 ml of an aqueous solution of 1M potassium hydrosulfate was hydrolyzed dropwise. Evaporate, remove with ethyl acetate, wash 2 times with an aqueous solution of 1M potassium hydrogen sulfate, then with a saturated aqueous solution of sodium chloride. Dried over anhydrous sodium sulfate, then concentrated. 35 g of colored oil are obtained.

LC / MS: MH ⁺ = 217

NMR, 300 MHz (CDCl ₃ ), δ (ppm): 6.70-7.00 (m, 4H); 7.20-7.35 (m, 2H); 7.55 (t, 1H); 7.95 (d, 1H); 10.43 (s, 1H).

Example 1.4: 2-amino-5- [2- (4-fluorophenoxy) phenyl] thiazole-4-methylcarboxylate

To a solution of 35 g of 2- (4-fluorophenoxy) benzaldehyde obtained in step 1.3 in 400 ml of diethyl ether was added 30 g of methyldichloroacetate at 0 ° C., then 325 ml of a solution of sodium methylate (0.5 M) in methanol were added dropwise. After 1 h at 0 ° C, only diethyl ether was evaporated, while maintaining methanol, 11 g of thiourea were added and heated under reflux for 6 hours. The reaction mixture is evaporated to dryness, it is extracted with ethyl acetate and washed with a 10% aqueous solution of ammonium hydroxide, then with a saturated aqueous solution of sodium chloride. Dry the organic phase over anhydrous sodium sulfate, then concentrate it. 100 ml of diethyl ether is taken up and filtered through a glass filter. 30 g of a white solid are obtained.

LC / MS: MH ⁺ = 345

NMR, 300 MHz (CDCl ₃ ), δ (ppm): 3.70 (s, 3H); 5.55 (br s, 2H); 6.55-6.80 (m, 4H); 7.00 (d, 1H); 7.20 (t, 1H); 7.35-7.45 (m, 2H).

Example 1.5: 2- [2- (S) -pentanoylamino] amino-5- [2- (4-fluorophenoxy) phenyl] thiazole-4-methylcarboxylate

To 8.6 g of 2-amino-5- [2- (4-fluorophenoxy) phenyl] thiazole-4-methylcarboxylate obtained in step 1.4 in a solution in 200 ml of N, N-dimethylformamide at 0 ° C, 2 75 g of N-methylmorpholine, 14.30 g of PyBOP, then 5.97 g of (S) -BOK-norvaline. The reaction medium is allowed to return to room temperature, then it is stirred for 16 hours. After evaporation, the precipitate is removed with ethyl acetate and washed with 2 times with a saturated aqueous solution of sodium bicarbonate, 2 times with water, 1 time with an aqueous solution of 1M potassium hydrogen sulfate, then with a saturated aqueous solution of sodium chloride . Dry the organic phase over anhydrous sodium sulfate, then concentrate it. Chromatograph the residue on a silica gel column, eluting with a mixture of ethyl acetate and petroleum ether 3: 7 (v / v). 8.5 g of a white solid are obtained.

LC / MS: MH ⁺ = 544

NMR, 300 MHz (CDCl ₃ ), δ (ppm): 0.88 (t, 3H); 1.38 (s, 9H); 1.39-1.55 (2m, 2H); 1.75 (m, 2H); 3.35 (br s, 1H); 3.68 (s, 3H); 4.28 (m, 1H); 5.65 (d, 1H); 6.80-6.90 (m, 5H); 7.10 (t, 1H); 7.20-7.32 (m, 2H).

6.5 g of the product obtained above is stirred in a solution in 60 ml of trifluoroacetic acid at room temperature for 30 minutes, then it is evaporated, the precipitate is extracted with ethyl acetate and washed with 2 times with a saturated aqueous solution of sodium carbonate, then with a saturated aqueous solution of sodium chloride. The organic phase was dried over anhydrous sodium sulfate, then it was evaporated to give 3.9 g of a white solid.

LC / MS: MH ⁺ = 444

Example 1.6: 2- {2- (S) - [2- (3,5-difluorophenyl) acetylamino] pentanoyl} amino-5- [2- (4-fluorophenoxy) phenyl] thiazole-4-methylcarboxylate

To 0.7 g of 2-amino-2- [2- (S) -pentanoylamino] -5- [2- (4-fluorophenoxy) phenyl] thiazole-4-methylcarboxylate obtained according to example 1.5, in a solution in 30 ml of N , N-dimethylformamide at 0 ° C add 0.20 g of N-methylmorpholine, 0.99 g of PyBOP, then 0.33 g of 3,5-difluorophenylacetic acid. The reaction medium is allowed to return to room temperature and it is stirred for 18 hours. The reaction medium is evaporated. The precipitate was recovered with ethyl acetate and washed 2 times with a saturated aqueous solution of sodium bicarbonate, 2 times with water, 1 time with an aqueous solution of 1M potassium hydrogen sulfate, then with a saturated aqueous solution of sodium chloride. Dry the organic phase over anhydrous sodium sulfate, then concentrate it. Chromatograph the residue on a silica column, eluting with 1: 1 (v / v) petroleum ether / ethyl acetate to give 0.56 g of a white solid.

LC / MS: MH ⁺ = 558

The NMR spectrum is described in the table (compound No. 13).

Example 2: 2- {2- (S) - [2- (S) -hydroxy- (3,3-dimethyl) butyrylamino] pentanoyl} amino-5- [2- (phenylthio) -3-pyridyl] thiazole-4 methyl carboxylate (compound No. 19)

Example 2.1: (2-phenylthio) -O, N-dimethylnicotinamide

(2-Phenylthio) -O, N-dimethylnicotinamide can be obtained according to the method similar to that described in step 1.2 of Example 1. Starting from 20 g of 2-phenylthionicotinic acid, 21.9 g of a colorless oil are obtained, which is subsequently used in this state.

LCD / MS: MH ⁺ = 275

NMR, 300 MHz (CDCl ₃ ), δ (ppm): 3.35 (br s, 3H); 3.58 (br s, 3H); 7.35 (m, 3H); 7.50 (m, 2H); 7.60 (d, 2H); 8.40 (d, 1H).

Example 2.2: (2-phenylthio) nicotinaldehyde

(2-Phenylthio) nicotinaldehyde can be obtained according to a method similar to that described in step 1.3 of Example 1. Starting from 21.9 g of (2-phenylthio) -O, N-dimethylnicotinamide (Weinreb amide (Weinreb)) obtained in step 2.1, and 48 ml of a solution of 1M lithium aluminum hydride in 300 ml of tetrahydrofuran give 16.6 g of a white solid.

NMR, 300 MHz (CDCl ₃ ), δ (ppm): 7.18 (m, 1H); 7.42 (m, 3H); 7.57 (m, 2H); 8.05 (d, 1H); 8.46 (d, 1H); 10.35 (s, 1H).

Example 2.3: 2-amino-5- [2- (phenylthio) -3-pyridyl] thiazole-4-methylcarboxylate (compound No. 19)

2-amino-5- [2- (phenylthio) -3-pyridyl] thiazole-4-methylcarboxylate can be obtained according to the method similar to that described in step 1.4 of example 1. Starting from 16.5 g of (2-phenylthio) nicotinaldehyde obtained in step 2.2, 11.2 g of methyldichloroacetate and 150 ml of 0.5 M sodium methylate in 300 ml of diethyl ether give 19 g of a pale yellow solid.

LCD / MS: MH ⁺ = 344

NMR, 300 MHz (DMSOd ₆ ), δ (ppm): 3.41 (br s, 3H); 3.60 (s, 3H); 7.20 (broad d, 1H); 7.38-7.48 (m, 5H); 7.65 (broad d, 1H); 8.30 (broad d, 1H).

Example 2.4: 2- [2- (S) -pentanoylamino] amino-5- [2- (phenylthio) -3-pyridyl] thiazole-4-methylcarboxylate

2- [2- (S) -pentanoylamino] amino-5- [2- (phenylthio) -3-pyridyl] thiazole-4-methylcarboxylate can be obtained according to the method similar to that described in stage 1.5 of example 1. Starting from 5.14 g of 2-amino-5- [2- (phenylthio) -3-pyridyl] thiazole-4-methylcarboxylate obtained in example 2.3, and 3.58 g of (S) -BOK-norvaline in the presence of 8.58 g of PyBOP and 1 66 g of N-methylmorpholine in N, N-dimethylformamide at 0 ° C. give, after chromatography, 3.5 g of a pale yellow solid.

LCD / MS: MH ⁺ = 542

NMR, 300 MHz (DMSOd ₆ ), δ (ppm): 0.87 (t, 3H); 1.45 (s, 9H); 1.70 (m, 2H); 1.97 (m, 2H); 3.72 (s, 3H); 4.45 (m, 1H); 5.23 (m, 1H); 7.10 (m, 1H); 7.30 (m, 3H); 7.42 (m, 2H); 7.50 (d, 1H); 8.39 (d, 1H).

Dissolve 3.5 g of the amine obtained above in 150 ml of a solution of 4M hydrochloric acid in 1,4-dioxane and 20 ml of methanol. Stirred for 1 h 30 min at room temperature, then evaporated. 3.2 g of a pale yellow solid are obtained.

LCD / MS: MH ⁺ = 442

Example 2.5: 2- {2- (S) - [2- (S) -hydroxy- (3,3-dimethyl) butyrylamino] pentanoyl} amino-5- [2- (phenylthio) -3-pyridyl] thiazole-4 methyl carboxylate

2- {2- (S) - [2- (S) -hydroxy- (3,3-dimethyl) butyrylamino] pentanoyl} amino-5- [2- (phenylthio) -3-pyridyl] thiazole-4-methylcarboxylate may be obtained according to a method similar to that described in step 1.6 of Example 1. Starting from 0.9 g of 2- [2- (S) -pentanoylamino] amino-5- [2- (phenylthio) -3-pyridyl] thiazole-4-methylcarboxylate obtained in stage 2.4, and 0.25 g of (S) -2-hydroxy-3,3-dimethylbutyric acid in the presence of 1 g of PyBOP and 0.59 g of N-methylmorpholine in 90 ml of N, N-dimethylformamide at 0 ° C get after chromatography on a column of silica gel eluted with a mixture of ethyl acetate / petroleum ether 7: 3 (vol./ b.), 0.5 g of a white powder.

LCD / MS: MH ⁺ = 557

The NMR spectrum is described in the table (compound No. 19).

Example 3: 2- {2- (S) - [2- (3,5-difluorophenyl) acetylamino] pentanoyl} amino-5- [2- (4'-trifluoromethyl) diphenyl] thiazole-4-methylcarboxylate (compound No. 5 )

Example 3.1: 2-amino-5- [2- (4'-trifluoromethyl) diphenyl] thiazole-4-methylcarboxylate

2-amino-5- [2- (4'-trifluoromethyl) diphenyl] thiazole-4-methylcarboxylate can be obtained according to a method similar to that described in stages 1.2-1.4 of example 1, starting from 26.6 g of 4-trifluoromethyl-2- diphenylcarboxylic acid. The Weinreb amide of this acid is reduced to the aldehyde with lithium aluminum hydride to give 18.7 g of a clear yellow oil. Aldehyde (18 g) is reacted with 10.3 g of methyldichloroacetate in the presence of 144 ml of 0.5 M sodium methoxide, then with 4.7 g of thiourea in methanol under reflux. 16 g of a pale yellow solid are obtained.

LC / MS: MH ⁺ = 379

Example 3.2: 2- [2- (S) -Pentanoylamino] amino-5- [2- (4'-trifluoromethyl) diphenyl] thiazole-4-methylcarboxylate

2- [2- (S) -Pentanoylamino] amino-5- [2- (4'-trifluoromethyl) diphenyl] thiazole-4-methylcarboxylate can be obtained according to the method similar to that described in step 1.5 of Example 1. Starting from 2.26 g of 2-amino-5- [2- (4'-trifluoromethyl) diphenyl] thiazole-4-methylcarboxylate obtained according to example 3.1, and 1.43 g of (S) -BOK-norvaline in the presence of 3.43 g of RuBOP and 0.66 g of N-methylmorpholine in 120 ml of N, N-dimethylformamide at ° C, obtained, after chromatography on a column of silica gel, eluting with a mixture of petroleum ether / ethyl acetate 8: 2 (vol./about.), 2 g of pale yellow solid matter.

LC / MS: MH ⁺ = 578

300 MHz NMR (CDCl ₃ ) δ (ppm): 0.92 (t, 3H); 1.45 (s, 9H); 1.70 (m, 2H); 1.80 (m, 2H); 3.69 (s, 3H); 4.40 (m, 1H); 5.10 (m, 1H); 6.98 (m, 4H); 7.27 (m, 2H); 7.32 (d, 2H).

Then, the resulting compound is deprotected with 50 ml of trifluoroacetic acid, following the method described in example 1.5. Get 1 g of white foam.

LC / MS: MH ⁺ = 478

Example 3.3: 2- {2 (S) - [2- (3,5-Difluorophenyl) acetylamino] pentanoyl} amino-5- [2- (4'-trifluoromethyl) diphenyl] thiazole-4-methylcarboxylate

2- {2 (S) - [2- (3,5-difluorophenyl) acetylamino] pentanoyl} amino-5- [2- (4'-trifluoromethyl) diphenyl] thiazole-4-methylcarboxylate can be prepared according to a method similar to that described in step 1.6 of Example 1. Starting from 0.94 g of 2- [2- (S) -pentanoylamino] amino-5- [2- (4'-trifluoromethyl) diphenyl] thiazole-4-methylcarboxylate obtained in step 3.2, and 0.18 g of 3,5-difluorophenylacetic acid in the presence of 0.55 g of RuBOP and 0.11 g of N-methylmorpholine in 50 ml of N, N-dimethylformamide at 0 ° C were obtained after chromatography on a column of silica gel eluted with ethyl acetate / petroleum ether 7: 3 (v / v), 0.45 g white powder.

LC / MS: MH ⁺ = 632

The NMR spectrum is described in the table (compound No. 5).

The table below illustrates the chemical structures and physical properties of several examples of compounds of the invention.

In the table:

- (S) or (R) in the columns “R ₃ ” and “R ₂ , R ₂ '” indicate the stereochemistry of an asymmetric carbon atom bearing R ₃ or R ₂ in the formula (I). For a carbon atom bearing R ₂ , the indication (S) or (R) does not apply to the case in which R ₂ and R ₂ 'together form an oxo group;

- MH ⁺ is the mass value of the compound protonated by a hydrogen atom (mass of the compound + 1) as determined by LC / MS.

The compounds of the invention were the subject of pharmacological tests that showed their usefulness as therapeutically active substances.

In particular, they were tested for their inhibitory effect on the production of β-amyloid peptide (β-A4).

The β-amyloid peptide (β-A4) is a fragment of a more important precursor protein called BPA (Amyloid Precursor Protein) (APP (Amyloid Precursor Protein)). This latter is produced and is present in various cells of animal or human tissue. However, its cleavage in the brain tissue by protease-type enzymes leads to the formation of β-A4 peptide, which accumulates in the form of amyloid plaques. Two proteases responsible for the production of amyloid peptide are known as beta-secretase and gamma-secretase (Wolf MS, Secretase targets for Alzheimer's disease: identification and therapeutic potential, J. Med. Chem., 2001, 44 (13), 2039- 60).

It has been shown that the aforementioned gradual deposition of the β-A4 peptide is neurotoxic and may play an important role in Alzheimer's disease.

Thus, the compounds of the present invention as an inhibitor of the production of β-amyloid peptide (β-A4) by inhibiting gamma secretase can be used in the treatment of pathologies such as senile dementia, Alzheimer's disease, Down syndrome, Parkinson's disease, amyloid angiopathy, and / or cerebrovascular disorders, frontotemporal dementia and Peak's disease, post-traumatic dementia, pathologies associated with inflammatory processes in the nervous system, Huntington's disease and Korsakov’s syndrome.

The tests were carried out according to the protocol described below.

For cell testing of β-amyloid, the CHO-K1 cell line is used, co-expressing CT100 from BPA (APP) and PS1 M146L clone 30-12. The cell line is aimed at inhibiting gamma secretase. Presenilin is associated with gamma secretase activity (Wolf MS, Haass C., The role of presenilins in gamma secretase activity, (J. Biol. Chem., 2001, 276 (8): 5413-6)) and its co-expression with amyloid protein or its N-terminal fragment leads to an increase in the secretion of peptide A1-42 (β-A4), thus generating a pharmacological tool that allows to evaluate the inhibition of the production of β-A4 peptide by the compounds of formula (I). Inoculation of 96-well culture plates was carried out at the rate of 1 × 10 ⁵ cells per well in 150 μl of incubation medium. The presence of a minimum percentage (1.3% final) of serum allows cell adhesion to plastic after 2-3 hours of incubation at 37 ° C in the presence of 5% CO ₂ . Products (15 μl) were tested with 10 μM 1% DMSO (final content) and incubated for 24-25 hours at 37 ° C in the presence of 5% CO ₂ at 100% humidity. After the mentioned 24-25 hour incubation, cell supernatants (100 μl) were transferred to ELISA plates treated with 6E10 capture antibodies (6E10, epitope: aa1-17, INTERCHIM / SENETEK 320-10) to determine the content of amyloid peptides secreted by cells in the presence of compounds according to the invention. In parallel, the gamma of the control synthetic peptide, “peptide 1-40”, is processed at concentrations of 5 and 10 ng / ml. ELISA plates are incubated overnight at 4 ° C.

The amount of bound peptide is detected indirectly in the presence of a competitor corresponding to a truncated peptide, peptide 1-28 bound to biotin, which is then detected using streptavidin bound to alkaline phosphatase. The substrate, p- nitrophenyl phosphate (pNPP FAST p-Nitrophenyl Phosphate, Sigma N2770), gives a clear, soluble yellow reaction product at 405 nm. The reaction is stopped with a solution of 0.1 M EDTA (EDTA). For this, after fixing the amyloid peptide in an ELISA plate, 50 μl of 1-28 biotinylated peptide is added to 100 μl of the settled cell fluid and incubated for 30 minutes at room temperature. Then the ELISA plates are washed 3 times. After drying by flipping on filter paper, 100 μl of streptavidin-alkaline phosphatase (Interchim / Jackson Immunoresearch Laboratories 016-050-084) was added to the well and incubated for 1 hour at room temperature. The plates are washed again, then alkaline phosphatase substrate (pNPP 1 mg / ml) is added at a rate of 100 μl per well. After incubation for 30 minutes at room temperature, the reaction is stopped by adding 100 μl of 0.1 M EDTA per well and read at 405 nm.

The most active compounds of formula (I) according to the present invention have a CE50 (concentration corresponding to an efficiency of 50%) of less than 500 nM, more specifically less than 100 nM. For example, compound No. 13 of the table has a CE50 of 6nM.

Biological test results show that the compounds are inhibitors of the formation of β-amyloid peptide (β-A4).

Therefore, these compounds can be used to treat pathologies in which an inhibitor of the formation of β-amyloid peptide (β-A4) provides therapeutic benefit. In particular, such pathologies include senile dementia, Alzheimer's disease, Down syndrome, Parkinson's disease, amyloid angiopathy, cerebrovascular disorders, frontotemporal dementia and Pick's disease, post-traumatic dementia, pathologies associated with inflammatory processes in the nervous system, Huntington's disease and Korsakov’s syndrome .

The use of the compounds of the invention for the manufacture of a medicament for the treatment of the aforementioned pathologies is an integral part of the invention.

Likewise, the subject of the invention is medicines which contain a compound of formula (I), or a salt of the addition of the latter with a pharmaceutically acceptable acid, or a hydrate or solvate of a compound of formula (I). These drugs are used in therapy, in particular in the treatment of the above pathologies.

According to another of its aspects, the present invention relates to pharmaceutical compositions containing, as active principle, at least one compound according to the invention. These pharmaceutical compositions comprise an effective dose of a compound of the invention, or a pharmaceutically acceptable salt, hydrate or solvate of the aforementioned compound, and, in known cases, one or more pharmaceutically acceptable excipients.

The aforementioned excipients are selected in accordance with the pharmaceutical form and the desired route of administration from conventional excipients known to those skilled in the art.

In the pharmaceutical compositions of the invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the aforementioned active principle of formula (I), its salt, its solvate or its possible hydrate can be administered in a single form of administration, in admixture with classical pharmaceutical excipients, animals and humans for the prophylaxis or treatment of the disorders or diseases mentioned above.

Suitable unit dosage forms include oral forms, such as tablets, soft or hard gelatine capsules, powders, granules, chewing gums and oral solutions or suspensions; forms for sublingual, buccal, intratracheal, intraocular, intranasal, inhalation, forms for subcutaneous, intramuscular or intravenous administration and forms for rectal or vaginal administration. For topical application, the compounds of the invention in the form of creams, lipsticks or lotions can be used.

As an example, a single tablet administration form of a compound of the invention may contain the following components:

- the compound according to the invention 50 mg;

- beckons 223.75 mg;

- sodium-containing croscaramellose 6.0 mg;

- corn starch 15.0 mg;

- hydroxypropyl methylcellulose 2.25 mg;

- magnesium stearate 3.0 m.

To obtain the desired prophylactic or therapeutic effect, the dose of the active principle may vary from 0.1 to 200 mg per kg of body weight per day. Although these dosages will be examples for the average situation, there may be special cases in which higher or lower dosages are used, such dosages equally belong to the invention. According to usual practice, the dosage corresponding to each patient is determined by the doctor according to the method of administration, weight and response of the aforementioned patient.

Each single dose may contain from 0.1 to 1000 mg, preferably from 0.1 to 500 mg of active principle in combination with one or more pharmaceutical excipients. The indicated single dose can be administered from 1 to 5 times a day so as to introduce a daily dose of from 0.5 to 5000 mg, preferably from 0.5 to 2500 mg.

In another aspect, the present invention also relates to a method for treating the pathologies mentioned above, which comprises administering a compound of the invention, a pharmaceutically acceptable salt or hydrate of the aforementioned compound.

Claims (6)

1. The compound corresponding to General formula (I)

in which R ₁ denotes C _1-6 -alkyl or phenyl; moreover, these phenyl groups are substituted by two substituents selected from halogen atoms;
R ₂ and R ₂ ′ are, independently of one another, a hydrogen atom or a hydroxy group;
R ₃ is C _1-6 alkyl;
one or the other of the radicals R ₄ and R ₅ represents a group Z

and one or the other of R ₄ and R ₅ represents a —C (X) R ₆ group;
G is a single bond;
Y represents a single bond, an oxygen atom, a sulfur atom, a C _1-4 alkylene group;
A and B denote, independently of one another, a hydrogen atom, halogen, trifluoromethyl, trifluoromethoxy group; provided that if Y is a single bond or an oxygen atom and if the Z group is a group of the type

then A is different from the hydrogen atom;
X represents an oxygen atom;
R ₆ is a C _1-6 alkoxy group;
in the form of a base or a pharmaceutically acceptable acid addition salt. 2. A method of obtaining a compound of formula (I) according to claim 1, comprising a step consisting in peptide binding of a compound of formula (IV)

with an amine of formula (VI)

in which R ₁ , R ₂ , R ₂ 'R ₃ , R ₄ , R ₅ are as defined in formula (I) according to claim 1. 3. A drug having the properties of an inhibitor of the formation of β-amyloid peptide (β-A4), characterized in that it contains a compound of formula (I) according to claim 1 in the form of a pharmaceutically acceptable base or salt. 4. A pharmaceutical composition having the properties of an inhibitor of the formation of β-amyloid peptide (β-A4), containing at least one compound of formula (I) according to claim 1 in the form of a pharmaceutically acceptable base or salt and, in known cases, one or more pharmaceutically acceptable excipients. 5. The compound of formula (I) according to claim 1, in the form of a pharmaceutically acceptable base or salt, for the manufacture of a medicament having the properties of an inhibitor of formation of a β-amyloid peptide (β-A4). 6. The use of the compounds of formula (I) according to claim 1 in the form of a pharmaceutically acceptable base or salt for the manufacture of a medicament for the treatment of senile dementia, Alzheimer's disease, Down syndrome, Parkinson's disease, amyloid angiopathy, cerebrovascular disorders, frontotemporal dementia and Peak’s disease, post-traumatic dementia, pathologies associated with inflammatory processes in the nervous system, Huntington’s disease and / or Korsakov’s syndrome.